Mechanisms of Homeostasis and Invasive Cell Migration in Skin Tumorigenesis

皮肤肿瘤发生中的稳态和侵袭细胞迁移机制

• 批准号: 8517009
• 负责人: Markus Schober
• 金额: $ 23.65万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517009
• 关键词: Anus; Apoptosis; Automobile Driving; Benign; Candidate Disease Gene; Carcinoma; Cell Survival; Cell-Matrix Junction; Cells; Data; Development; Disease; Disseminated Malignant Neoplasm; Epidermis; Epithelial; Epithelium; Equilibrium; Focal Adhesion Kinase 1; Focal Adhesions; Gene Expression; Genes; Genital system; Goals; Growth; Growth Factor; HRAS gene; Homeostasis; Human; Instruction; Integrins; Lead; Link; Literature; Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Mediating; Metastatic Carcinoma; Metastatic Squamous Cell Carcinoma; Molecular; Molecular Target; Mus; Mutant Strains Mice; Neoplasm Metastasis; Pathway interactions; Play; Probability; Proteomics; Receptor Protein-Tyrosine Kinases; Reporting; Role; Signal Transduction; Skin; Skin Carcinogenesis; Skin Carcinoma; Squamous cell carcinoma; Technology; Testing; Therapeutic; Tissues; Transcription Factor 3; Transducers; Tumor Cell Line; Tumor Markers; Tumor Suppressor Genes; Tyrosine; adhesion receptor; base; carcinogenesis; cell motility; combinatorial; human disease; keratinocyte; migration; neoplastic; novel; novel therapeutic intervention; prevent; programs; receptor; research study; therapeutic target; tumor; tumor initiation; tumor progression; tumorigenesis

The long term goal of this proposal is to understand how growth promoting and restricting signals interact to balance one another and how their deregulation leads to the development of neoplastic tumors which often turn into malignant, metastatic carcinomas. My preliminary data revealed that loss of TGF-(3 receptor 11 (TpRll) function in the skin epithelium produces spontaneous anal and genital squamous cell carcinomas (SCCs) and cooperates with active H-Ras to form metastatic SCCs. Focal adhesion kinase (FAK) mediated integrin signaling is hyperactive in these carcinomas and cultured keratinocytes suggesting a direct link between TpRIl loss and FAK activation. Indeed, FAK has been reported to be the most commonly hyperactivated non receptor tyrosine kinase in epithelial tumors and tumor cell lines, yet its functions and molecular targets are largely unknown. The central hypothesis tested by this proposal is that FAK plays a central role in the development of SCCs in T(3Rii deficient skin epithelium. This hypothesis will be tested experimentally by: 1) assessing the probabilities to develop spontaneous anal and genital, or chemically induced SCCs in skin of WT, TpRll and FAK single and TpRll/FAK double conditional mutant mice and investigating the underlying cellular and pathological alterations; 2) identification of molecular mechanisms by which loss of TpRll function in keratinocytes promotes FAK activation; and 3) investigate how loss of TpRll and increased FAK activity promote skin carcinogenesis, malignant progression, and invasive metastatic keratinocyte migration. Data generated from the proposed experiments will advance our understanding of the molecular functions of TpRlliand FAK mediated integrin signaling in normal development and disease, identify the molecular mechanisms by which growth promoting Ras and Integrin signaling interact with growth restrictihg TGF-p signaling to control not only proliferation, but also ceil survival, cytoskeletal dynamics and invasive cell migration, and identify novel molecular pathways by which carcinomas form even in the absence of FAK fiintion. Together, this proposal will strengthen our molecular and cellular understanding of carcinoQehesis and will reveal potential therapeutic targets. .

这项提案的长期目标是了解促进增长和限制增长的信号如何相互作用 以及它们的放松管制如何导致肿瘤的发展，这种肿瘤通常 变成了恶性的、转移性的癌症。我的初步数据显示，转化生长因子-3受体11的丢失 皮肤上皮(TpRll)功能导致自发性肛门和生殖器鳞状细胞癌 (SCCS)，并与活性H-RAS协同作用形成转移性SCCs。粘着斑激酶(FAK)介导的信号转导 整合素信号在这些癌细胞和培养的角质形成细胞中过度活跃，提示有直接联系 在TpRIl丢失和FAK激活之间。事实上，据报道，FAK是最常见的过度激活 非受体酪氨酸激酶在上皮性肿瘤和肿瘤细胞系中的作用 分子目标在很大程度上是未知的。这一提议检验的中心假设是FAK扮演着一个 在T(3Rii缺乏的皮肤上皮中SCCs的发育中起中心作用。这一假设将得到检验。 实验方法：1)评估自发性肛门和生殖器发育的可能性，或通过化学方法 WT、TpRll、FAK单条件突变和TpRll/FAK双条件突变小鼠皮肤SCCs的诱导 研究潜在的细胞和病理改变；2)分子机制的鉴定 角质形成细胞中TpRll功能的丧失如何促进FAK的激活；以及3)研究TpRll功能的丧失如何促进FAK的激活 TpR11和FAK活性增加促进皮肤癌变、恶性进展和侵袭性 转移性角质形成细胞迁移。从拟议的实验中产生的数据将推动我们的 正常人TpR11和FAK介导的整合素信号分子功能的研究 发育和疾病，确定生长促进RAS和整合素的分子机制 信号与生长抑制的转化生长因子-β信号相互作用，不仅控制细胞增殖，而且还控制细胞 存活、细胞骨架动力学和侵袭性细胞迁移，并确定新的分子途径，通过这些途径 即使在没有FAK活性的情况下，癌症也会形成。总之，这项提议将加强我们的分子 以及细胞对癌症的了解，并将揭示潜在的治疗靶点。。